KR20030045672A - Process for producing aspartyl dipeptide ester derivatives - Google Patents

Abstract

N- [N- [3- (which is expected as a sweetener by reductively alkylating aspartame with 3- (phenyl) -2-propenylaldehyde having a substituent specific to the benzene ring in the presence of a catalyst and a base and hydrogen. Provided is a method for producing phenyl) propyl] -L-α-aspartyl] -L-phenylalanine 1-methyl ester derivative having various substituents on a benzene ring in an industrially simple and good yield.

Description

Process for producing aspartyl dipeptide ester derivatives

In recent years, as the diet has been advanced, obesity and various diseases caused by excessive sugar intake have become a problem, and development of low-calorie sweeteners replacing sugar is strongly desired. At present, aspartame, which is widely used as a sweetener in terms of safety and sweetness, has some problems in terms of stability. In view of the above, according to some of the inventors, various specific substituents on N- [N- (benzene rings as sweeteners having excellent stability and much higher sweetness, that is, superior in sweetener price. Phenylpropyl) -L-α-aspartyl] -L-phenylalanine 1-methyl ester (aspartame derivative) having been found (see WO 99/52937), but it is known about its efficient preparation method. It is not. N- [N- (3-phenylpropyl) -L-α-aspartyl] -L-phenylalanine 1-methyl ester or N- [N- (3-methoxy-4-) that is less sweet compared to these compounds Although hydroxyphenylpropyl) -L-α-aspartyl] -L-phenylalanine 1-methyl ester is described in International Patent Publication No. WO 94/11391, examples showing which raw materials are used to synthesize And no mention is made of its preparation.

Problem of invention

By the way, some of the inventors of the present invention catalyze aspartame and 3- (phenyl) -2-propenylaldehyde having various substituents on the benzene ring as an excellent production method in aspartame derivatives that can be used as sweeteners. A method for producing by reductively alkylating with hydrogen in the presence of is proposed and filed by the same applicant as the present patent application (see Japanese Patent Application No. Hei 11-287398, PCT / JP00 / 06626 specification). ]. However, there is still room for further improvement in yield.

The problem to be solved by the present invention is an aspartyl dipeptide ester derivative of formula II, more specifically N- [N- (phenylpropyl having a variety of specific substituents on the benzene ring) -L-α-aspartyl] It is to provide a method for producing industrially simple and efficient -L-phenylalanine 1-methyl ester (aspartame derivative).

The present invention relates to a novel process for preparing aspartyl dipeptide ester derivatives expected as sweeteners.

Disclosure of the Invention

The present inventors have diligently studied how to efficiently prepare a compound of formula (II). As a result, aspartame is reductively alkylated with hydrogen and an aldehyde of formula (I) in the presence of a base and a catalyst. It was found that the desired aspartyl dipeptide ester derivative of formula (II) was easily obtained by neutralization by means of the present invention to complete the present invention.

That is, this invention exists in the following content.

[1] A process for preparing an aspartyl dipeptide ester derivative of formula (II), wherein aspartame is alkylated reductively with hydrogen and an aldehyde of formula (I) in the presence of a catalyst and a base.

The derivative may be in any form in the vitreous and salts. Thus, it can be obtained by the production of the desired compound in the form of a salt by a reductive alkylation process, and if necessary can be obtained by converting it back into the vitreous to produce the desired compound, all of which are included in the invention. In the present invention, in addition to the reductive alkylation reaction step, a conventional salting step, desalting step, purification step, and the like can be added in a range that does not impair the object thereof.

In Formula I above,

R ₁ , R ₂ , R ₃ , R ₄ and R ₅ are each independently a hydrogen atom, a hydroxyl group (wherein the hydroxyl group may represent a substituent in the form of a hydrogen atom substituted with a metal atom), and 1 to 3 carbon atoms A substituent selected from an alkoxy group, an alkyl group having 1 to 3 carbon atoms, a benzyloxy group and a hydroxyalkyloxy group having 2 or 3 carbon atoms,

R ₁ and R ₂ or R ₂ and R ₃ together may form a methylenedioxy group.

In Formula II above,

R ₁ , R ₂ , R ₃ , R ₄ and R ₅ are each independently a hydrogen atom, a hydroxyl group (wherein the hydroxyl group may represent a substituent in the form of a hydrogen atom substituted with a metal atom), and 1 to 3 carbon atoms A substituent selected from an alkoxy group, an alkyl group of 1 to 3 carbon atoms and a hydroxyalkyloxy group of 2 or 3 carbon atoms,

R ₁ and R ₂ or R ₂ and R ₃ together may form a methylenedioxy group.

In addition, in the case of having the benzyloxy group in the aldehyde used in the above starting materials, in the reaction of the present invention, benzyloxy is converted to hydroxyl group by debenzylation of the benzyl group of the benzyloxy moiety and obtained in the target compound obtained after the reaction. It does not have a group and instead has a hydroxyl group.

[2] The method of [1], wherein the derivative obtained as the target compound is a vitreous.

In this case, a process of converting the salt of the derivative obtained by the reductive alkylation reaction into the vitreous is included.

[3] In the general formula (I), R ₁ , R ₂ , R ₃ , R ₄ and R ₅ each independently represent a substituent selected from a hydrogen atom, a hydroxyl group, a methoxy group, a methyl group and a benzyloxy group, and In formula (II), R ₁ , R ₂ , R ₃ , R ₄ and R ₅ each independently represent a substituent selected from a hydrogen atom, a hydroxyl group, a methoxy group and a methyl group.

[4] In the above method, the aldehyde of the starting material has a hydroxyl group on a benzene ring or the like, at least a part of the hydrogen atoms of these hydroxyl groups is substituted with a metal atom, and the hydroxyl group is at least part of the metal alkoxylated aldehydes. The method of [1] to [3], wherein is present as a base.

In the present invention, when the aldehyde has a hydroxyl group, the metal alkoxylation may act as a base, and thus it is not necessary to add and use a separate base. The base is not preferable because excessive use causes side reactions.

[5] In Formulas I and II, R ₁ is a hydrogen atom, a methyl group or a hydroxyl group, R ₂ is a hydrogen atom, a methyl group or a hydroxyl group, R ₃ is a methoxy group, R ₄ and R ₅ is a hydrogen atom. Provided that at least one of R ₁ and R ₂ may be a benzyloxy group. Here, in particular, in the above formula, R ₂ is a hydrogen atom or a hydroxyl group, R ₃ is a methoxy group, and R ₁ , R ₄ and R ₅ are hydrogen atoms, in particular the methods of [1] to [4] This is preferred. Among these, the method in which R ₁ , R ₄ and R ₅ are hydrogen atoms, R ₂ is a hydroxyl group, and R ₃ is a methoxy group, particularly the methods of [1] to [4] is more preferable.

[6] In Formulas I and II, R ₁ is a hydrogen atom, a methyl group or a methoxy group, R ₂ is a hydrogen atom, a methyl group or a methoxy group, R ₃ is a hydroxyl group, R ₄ and R ₅ is a hydrogen atom. In formula (I), R ₃ may be a benzyloxy group. In particular, in the above formula, R ₂ is a hydrogen atom or a methoxy group, R ₃ is a hydroxyl group, and R ₁ , R ₄ and R ₅ are hydrogen atoms, in particular the methods of [1] to [4] This is preferred.

[7] The method wherein the base is at least one base selected from metal hydrides, metal alkoxides, metal hydroxides and amines, in particular the methods of [1] to [3].

[8] The metal hydrides are LiH, NaH, KH and the like, the metal alkoxides are LiOMe, NaOMe, KOMe and the like, the metal hydroxides are LiOH, NaOH, KOH and Mg (OH) ₂ , and the base is at least one of them [7] Way.

[9] The method of [7], wherein the amine is at least one of Et ₃ N and Et ₂ NH.

[10] The method wherein the base is sodium hydroxide or potassium hydroxide, in particular the method of [1] to [3].

[11] A method including a step of premixing a base and an aldehyde, in particular, the method of [1] to [3].

[12] The method comprising the step of converting an aldehyde to a compound of formula III or IV, or to a compound of formula III or IV, in particular the method of [1] to [4].

In Formulas III and IV above,

X is any one of lithium atom, sodium atom and potassium atom,

Me is a methyl group.

In this method, aldehydes can also serve as bases, so that no additional (new) base needs to be added and used during reductive alkylation with aspartame.

[13] The base is any one of a lithium compound, a sodium compound, and a potassium compound, and an aldehyde is a compound of the following formula III 'or IV', wherein the aldehyde and the base are premixed to form a salt of the following formula III or IV. The method including a process, especially the method of [1]-[4].

Formula III

Formula IV

In the above formulas III, IV, III 'and IV',

X is any one of lithium atom, sodium atom and potassium atom,

Me is a methyl group.

Equally, in the process of the present invention, since the aldehyde can also serve as a base, it is not necessary to add and use a separate base in the reductive alkylation reaction with aspartame.

[14] A method comprising neutralizing a salt of a derivative obtained by the reductive alkylation reaction with an acid to convert the salt of the derivative into a vitreous body, particularly the method of [1] to [4].

[15] The method of [14], wherein the acid is any one of hydrochloric acid, sulfuric acid and acetic acid.

[16] The method of [14], wherein the neutralization by acid in the reductive alkylation reaction is carried out during the hydrogenation reaction.

[17] The method in which the hydrogenation reaction temperature in the reductive alkylation reaction is 0 to 60 ° C, in particular the method of [1] to [4].

[18] A method comprising the step of maintaining stirring at 40 DEG C or lower for at least 10 minutes prior to the hydrogenation reaction in the reductive alkylation reaction, in particular the method of [1] to [4].

[19] A method comprising the step of removing at least a portion of water in a solvent prior to hydrogenation in a reductive alkylation reaction, in particular the method of [1] to [4].

[20] The method wherein the catalyst is a hydrogenation catalyst and is at least one of palladium carbon, palladium black, Raney nickel and platinum carbon, in particular the method of [1] to [4].

[21] The method wherein the reaction is carried out in a solvent, particularly the method of [1] to [4].

[22] The method of [21], wherein the solvent is an alcohol, particularly methanol or a mixed solvent of methanol (such as methanol as a function).

[23] A method comprising a hydrogenation reaction at a hydrogen partial pressure of 0.1 to 10, preferably 0.1 to 1.0 MPa in a reductive alkylation reaction, in particular the method of [1] to [4].

[24] The method comprising the step of crystallizing the derivative with a water-alcohol mixed solvent after the derivative of the target compound is a vitreous and generates the vitreous, in particular, the method of [1] to [4].

By this crystal precipitation method, salts can be efficiently removed and separated.

[25] The method of [24], wherein the alcohol used for the crystal precipitation solvent (mixed solvent) is methanol.

Embodiment

EMBODIMENT OF THE INVENTION Hereinafter, embodiment is described regarding this invention. In addition, the description will be made based on a representative method, and the present invention includes, but is not limited to, this.

In the method of the present invention, a solution in which aspartame and a specific aldehyde are dissolved or dispersed in the presence of a base is maintained at a suitable temperature for a predetermined time, followed by addition of a catalyst (such as a hydrogenated catalyst) and stirring in a hydrogen gas atmosphere (hydrogen). The reaction proceeds only with addition). In this way the desired derivative can be obtained in the form of a salt. In the case of obtaining the vitreous, neutralization is carried out by addition of an acid during or after the completion of the hydrogenation reaction, and the filtrate is concentrated after filtration and fractionation of the catalyst to obtain crude aspartyl dipeptide derivatives. By purification, the desired aspartyl dipeptide derivative (free body) can be easily obtained.

In addition, since decomposition of aspartame proceeds under basic conditions, it is also preferable to add aspartame to a solution in which aldehyde and base are mixed in advance to prevent decomposition of aspartame. At this time, with respect to the aldehyde having a hydroxyl group, especially a phenolic hydroxyl group, the phenolic hydroxyl group is used as a salt such as phenoxide in advance to exhibit an alkylation reaction with aspartame without newly adding a base. Can be. This method is preferable in that it can suppress side reactions, for example, the production of diketopiperadine of aspartame. Such a method is naturally also included in the present invention.

There is no particular limitation regarding the base used, and compounds corresponding to bases (inorganic bases, organic bases, etc.) can be used. As a base, it can select from a metal hydride, a metal alkoxide, a metal hydroxide, and an amine, for example. Examples of the metal hydride include LiH, NaH, and KH. Examples of the metal hydride include LiOMe, NaOMe, and KOMe. Examples of the metal hydroxide include LiOH, NaOH, KOH, Mg (OH) ₂ , and the like. Of these, inorganic bases such as sodium carbonate, sodium hydrogen carbonate, sodium hydroxide, lithium hydroxide, potassium hydroxide, magnesium hydroxide, sodium hydride, sodium methoxide, and triethylamine, diethyl, because they can be industrially inexpensive. Organic amines, such as an amine, are used preferably. In particular, sodium hydroxide and potassium hydroxide are preferably used.

In the reductive alkylation reaction in the present invention, if the pH value of the solution before the hydrogenation reaction for reacting hydrogen is too low, the decomposition reaction proceeds, so 6.5 or more is preferable. More preferably, the pH value is about 7.5-12.

In the present invention, in the reductive alkylation reaction, the reaction is preferably maintained at a temperature of 50 ° C. or lower for at least 10 minutes and more preferably at about −10 to 40 ° C. for about 2 to 3 hours before the hydrogenation reaction. It is preferable in terms of prevention.

Regarding stirring and holding before the hydrogenation reaction, the solvent can be more effectively carried out by concentrating the solvent and dehydrating the inside of the system. In the method of the present invention, it is believed that the Schiff base generation reaction between aldehyde and aspartame is promoted. As regards the water content in the solvent, it may be preferably 10% by weight or less, more preferably about 5 to 0.1% by weight.

Also, in the solvent used, it is preferable to use one having a low moisture content.

As a method of dehydration, a dehydrating agent can be added. For example, zeolite, a "molecular sieve", etc. can be added and dewatered.

The temperature and time of the reaction may be selected as appropriate conditions in the hydrogenation reaction as a reductive alkylation reaction, but to promote a reaction aimed at suppressing side reactions, it is preferably in the temperature range of about 0 to 40 ° C., about 2 to 72 hours. Reaction time, more preferably a temperature range of about 10 to 30 ℃, a reaction time of about 10 to 48 hours can be selected.

When the desired compound is obtained as a free body, a neutralization process is required but there are no particular restrictions on the acid used for neutralization. The inorganic acid and organic acid which are used normally can be used. Acetic acid, hydrochloric acid, sulfuric acid, etc. are preferable at the point which can be industrially inexpensive.

When the desired derivative is obtained in the form of a free body, neutralization with an acid in the present invention is not limited to the end of the hydrogenation reaction, and may be during the hydrogenation reaction. In this way, the yield can be further improved by adjusting the inside of the system to acidic or neutral. In this case, it is preferable to adjust acidic or neutral after reaction passes for a predetermined time from the start of hydrogenation reaction, for example, it carries out within 50 hours at 50 degrees C or less. Preferably at about 0 to 35 ℃ can be carried out after about 1 to 6 hours. It is also preferable to carry out after 2 to 5 hours to suppress decomposition reactions of raw materials and products.

As such, when an acid is added during the hydrogenation reaction, the reaction can be continued for about 15 to 48 hours at a temperature of about 10 to 50 ° C in the subsequent reaction.

The pH value of the reaction solution after neutralization is preferably about 2 to 8, more preferably about 3 to 7 in order to suppress decomposition of the product.

The solvent used for the reductive alkylation reaction in the present invention is not particularly limited as long as it is inert to the reaction substrate, the catalyst and the product, and a homogeneous organic solvent for dissolving the aldehyde used in the aspartame and the starting material (using one type) Single solvent or mixed solvent using a plurality) or a mixed solvent of such an organic solvent and water. As an organic solvent, alcohols, such as methanol and ethanol, tetrahydrofuran, toluene, methyl acetate, and dimethylformamide, are mentioned, for example. Methanol is mentioned as a especially preferable solvent.

As a catalyst, a palladium type catalyst, a platinum type catalyst, a nickel type catalyst, etc. are mentioned. Specifically, palladium carbon, palladium black, Raney nickel, platinum carbon, etc. are mentioned. In particular, palladium-based catalysts such as palladium carbon and palladium black are preferable. The reductive alkylation reaction can be carried out by hydrogenation, and as the hydrogen pressure at this time, preferably about 0.1 to 10 MPa, more preferably about 0.1 to 1 MPa can be selected.

When performing the reductive alkylation reaction at atmospheric pressure, a method of bubbling hydrogen into the reaction solution is preferable in terms of reaction promotion.

Regarding the molar ratio of aspartame and aldehyde used as the raw material for the reaction, the reaction can be carried out in the range of preferably about 0.5 to 3, more preferably about 1 to 2.

In the present invention, the desired derivative can be obtained in the form of a salt or a free body after the completion of the reductive alkylation reaction, but the salting step, the desalting step or the processes and means necessary for the separation and purification thereof can be easily carried out according to a conventional method. . It goes without saying that all of the derivatives obtained as described above are included in the material produced according to the method of the present invention.

In particular, when the target compound is separated and purified in the form of a vitreous body, salts can be efficiently removed by crystallizing the target compound by using water-alcohol (methanol or the like) as the crystal precipitation solvent.

Invention

From the findings of the present inventors, the yield is low in the alkylation reaction with aspartame and 3- (phenyl) -2-propenylaldehyde having various substituents on the benzene ring. This is thought to be due to the unstable decomposition of the Schiff base formed upon hydrogenation or the occurrence of side reactions (alcohol production) of the aldehyde. In the present invention, the Schiff salt is stably formed by the presence of a base in the reaction system. It is thought that hydrogenation aiming at the suppression of is accelerated.

Hereinafter, an Example demonstrates this invention in detail.

(Example 1)

Preparation of N- [N- [3- (3-hydroxy-4-methoxyphenyl) propyl] -L-α-aspartyl] -L-phenylalanine 1-methyl ester

3.12 g (10.2 mmol) of aspartame and 0.45 g (10.8 mmol) of sodium hydroxide pellets are added to 100 ml of methanol and stirred at 30 ° C. for 10 minutes. 1.51 g (8.59 mmol) of 3- (3-hydroxy-4-methoxyphenyl) -2-propenylaldehyde was added to the solution, followed by 0.9 g of 10% palladium carbon (dried), followed by atmospheric pressure (0.1 MPa). Stir for 47 hours at 35 ° C. under a hydrogen atmosphere. The reaction solution was filtered to remove the catalyst, the filtrate was neutralized with acetic acid and then quantified by HPLC (high performance liquid chromatography) to yield 2.04 g (4.45 mmol, 51.8%) of the title compound.

(Example 2)

Preparation of N- [N- [3- (3-hydroxy-4-methoxyphenyl) propyl] -L-α-aspartyl] -L-phenylalanine 1-methyl ester

Pellet sodium hydroxide 0.87g (20.9mmol) and 3- (3-hydroxy-4-methoxyphenyl) -2-propenylaldehyde 3.0g (17.0mmol) were added to 200ml of methanol and stirred for a while to completely dissolve. . 5.82 g (19.8 mmol) of aspartame was added at room temperature, followed by slurrying, and 80 g of methanol was distilled off under reduced pressure. Subsequently, 0.77 g of 10% palladium carbon (dried product) was added thereto, stirred at room temperature under a hydrogen atmosphere at atmospheric pressure (0.1 MPa) for 3 hours, and then 1.72 ml (29.0 mmol) of acetic acid was added, followed by hydrogen atmosphere at atmospheric pressure (0.1 MPa). Stir at 45 ° C. for 21 hours. The reaction solution was filtered to remove the catalyst, and the filtrate was quantified by HPLC (high performance liquid chromatography) to give 4.18 g (9.12 mmol, 53.6%) of the title compound.

(Example 3)

Preparation of N- [N- [3- (3-hydroxy-4-methoxyphenyl) propyl] -L-α-aspartyl] -L-phenylalanine 1-methyl ester

Pellet sodium hydroxide 0.87g (20.9mmol) and 3- (3-hydroxy-4-methoxyphenyl) -2-propenyl aldehyde 3.0g (17.0mmol) were added to 100ml of methanol and stirred for a while to completely dissolve. . 5.82 g (19.8 mmol) of aspartame was added at room temperature, followed by stirring at 35 ° C. for 3 hours. Subsequently, 0.87 g of 10% palladium carbon (dried) was added thereto, followed by stirring for 22 hours at 10 ° C. under a hydrogen atmosphere of atmospheric pressure (0.1 MPa), followed by addition of 1.72 ml (29.0 mmol) of acetic acid, followed by a hydrogen atmosphere of atmospheric pressure (0.1 MPa). Stir at 35 ° C. for 21 h. The reaction solution was filtered to remove the catalyst, and the filtrate was quantified by HPLC (high performance liquid chromatography) to yield 4.95 g (10.8 mmol, 63.5%) of the title compound.

(Example 4)

Preparation of N- [N- [3- (3-hydroxy-4-methoxyphenyl) propyl] -L-α-aspartyl] -L-phenylalanine 1-methyl ester

2.7 g (64.8 mmol) of sodium hydroxide pellets and 9.11 g (51.0 mmol) of 3- (3-hydroxy-4-methoxyphenyl) -2-propenylaldehyde were added to 314 ml of methanol and stirred for a while to completely dissolve. . After adding 18.1 g (61.4 mmol) of aspartame at room temperature, the mixture was stirred at 10 ° C. for 3 hours. Subsequently, 2.7 g of 10% palladium carbon (dried product) was added and stirred at 10 ° C. for 6 hours while bubbling the reaction solution at a hydrogen flow rate of 50 ml / min, followed by adding 5.35 g (89.0 mmol) of acetic acid, followed by atmospheric pressure (0.1 Stir for 17 h at 35 ° C. under a hydrogen atmosphere of MPa). The reaction solution was filtered to remove the catalyst, and the filtrate was quantified by HPLC (high performance liquid chromatography) to yield 16.4 g (35.8 mmol, 70.1%) of the title compound.

(Example 5)

Preparation of N- [N- [3- (3-hydroxy-4-methoxyphenyl) propyl] -L-α-aspartyl] -L-phenylalanine 1-methyl ester crystals

After distilling off the solvent under reduced pressure of the reduction reaction solution obtained in Example 4, 250 ml of a methanol-water mixed solvent (33% by volume) was added, followed by stirring for a while at 60 ° C to completely dissolve the residue. Subsequently, the crystals are precipitated by sequentially cooling to 10 ° C. Thereafter, the crystals obtained by aging at this temperature for 13 hours were filtered off and dried to obtain N- [N- [3- (3-hydroxy-4-methoxyphenyl) propyl] -L-α-aspartyl 12.7 g of crystals of] -L-phenylalanine 1-methyl ester are obtained.

(Example 6)

Preparation of N- [N- [3- (4-hydroxy-3-methoxyphenyl) propyl] -L-α-aspartyl] -L-phenylalanine 1-methyl ester

Pellets of sodium hydroxide 0.86 g (20.64 mmol) and 3.00 g (16.7 mmol) of 3- (4-hydroxy-3-methoxyphenyl) -2-propenylaldehyde were added to 105 ml of methanol and stirred for a while to completely dissolve. . Aspartame 6.1g (20.7mmol) was added at 10 ° C, and stirred for 2.5 hours as it is. Subsequently, 1.89 g of 10% palladium carbon (50% hydrous) was added and stirred for 5 hours at 10 ° C. under a hydrogen atmosphere of 0.7 MPa, followed by 1.62 mL (27.2 mmol) of acetic acid, followed by 0.7 MPa hydrogen atmosphere at 35 ° C. for 12 hours. Stir under. The reaction solution was filtered to remove the catalyst, and the filtrate was quantified by HPLC to yield 5.05 g (11.0 mmol, 660%) of the title compound.

(Comparative Example 1)

Preparation of N- [N- [3- (3-hydroxy-4-methoxyphenyl) propyl] -L-α-aspartyl] -L-phenylalanine 1-methyl ester

0.40 g (1.47 mmol) of aspartame and 0.25 g (1.40 mmol) of 3- (3-hydroxy-4-methoxyphenyl) -2-propenylaldehyde were added to 13 ml of methanol and stirred for a while. 0.12 g of 10% palladium carbon (50% hydrous) was added to the slurry and stirred for 24 hours at room temperature under a hydrogen atmosphere at atmospheric pressure (0.1 MPa). The reaction solution was filtered to remove the catalyst, and the filtrate was quantified by HPLC (high performance liquid chromatography) to yield 0.21 g (0.46 mmol, 32.8%) of the title compound.

According to the invention, aspartyl dipeptide ester derivatives expected as sweeteners, i.e., N- [N- [3- (phenyl) propyl] -L-α-aspartyl having the various substituents on the benzene ring) -L-phenylalanine 1-methyl ester derivative can be produced industrially simple and with good yield.

Claims (21)

A process for the preparation of aspartyl dipeptide ester derivatives of formula (II), which may be in the form of a vitreous or salt, characterized by reductively alkylating aspartame with aldehyde of formula (I) and hydrogen in the presence of a catalyst and a base. Formula I In Formula I above, R ₁ , R ₂ , R ₃ , R ₄ and R ₅ are each independently a hydrogen atom, a hydroxyl group (wherein the hydroxyl group may represent a substituent in the form of a hydrogen atom substituted with a metal atom), and 1 to 3 carbon atoms A substituent selected from an alkoxy group, an alkyl group having 1 to 3 carbon atoms, a benzyloxy group and a hydroxyalkyloxy group having 2 or 3 carbon atoms, R ₁ and R ₂ or R ₂ and R ₃ together may form a methylenedioxy group. Formula II In Formula II above, R ₁ , R ₂ , R ₃ , R ₄ and R ₅ are each independently a hydrogen atom, a hydroxyl group, an alkoxy group having 1 to 3 carbon atoms, an alkyl group having 1 to 3 carbon atoms and a hydroxyalkyloxy having 2 or 3 carbon atoms A substituent selected from the group, R ₁ and R ₂ or R ₂ and R ₃ together may form a methylenedioxy group. The method according to claim 1, wherein in formula (I) R ₁ , R ₂ , R ₃ , R ₄ and R ₅ are each independently a hydrogen atom, a hydroxyl group (wherein the hydroxyl group is a substituent in the form of a hydrogen atom substituted with a metal atom) And a substituent selected from a methoxy group, a methyl group and a benzyloxy group, wherein in Formula II, R ₁ , R ₂ , R ₃ , R ₄ and R ₅ are each independently a hydrogen atom, a hydroxyl group, a methoxy group To a substituent selected from a oxy group and a methyl group. A compound according to claim 1 or 2, wherein in formula (I) and (II), R ₁ is a hydrogen atom, a methyl group or a hydroxyl group, R ₂ is a hydrogen atom, a methyl group or a hydroxyl group, and R ₃ is a methoxy group And R ₄ and R ₅ are hydrogen atoms provided that at least one of R ₁ and R ₂ in formula (I) can be a benzyloxy group. A compound according to claim 1 or 2, wherein in formula (I) and (II), R ₁ is a hydrogen atom, a methyl group or a methoxy group, R ₂ is a hydrogen atom, a methyl group or a methoxy group, and R ₃ is a hydroxyl group And R ₄ and R ₅ are hydrogen atoms provided that in formula (I) R ₃ may be a benzyloxy group. A compound according to claim 1 or 2, wherein in formulas I and II, R ₁ , R ₄ and R ₅ are hydrogen atoms, R ₂ is a hydroxyl group, R ₃ is a methoxy group, provided that _{The divalent} benzyloxy group. The method according to any one of claims 1 to 5, wherein the aspartyl dipeptide ester derivative is a vitreous and includes converting a salt of the derivative to a vitreous. The aldehyde of claim 1, 2 or 6, wherein the aldehyde has a hydroxyl group, at least some of the hydrogen atoms of the hydroxyl groups are substituted with metal atoms, and the hydroxyl group is at least one of the metal alkoxylated aldehydes. Wherein some are present as bases. The method of claim 1, 2 or 6, wherein the base is sodium hydroxide or potassium hydroxide. 7. The method of claim 1, 2 or 6 comprising the step of premixing the base and the aldehyde. 8. The method of claim 1, 2, 6 or 7, wherein the aldehyde is a compound of formula III or IV, or comprises a step of converting to a compound of formula III or IV. Formula III Formula IV In Formulas III and IV above, X is any one of a lithium atom, a sodium atom and a potassium atom. The method according to claim 1, 2, 6 or 7, wherein the base is any one of a lithium compound, a sodium compound and a potassium compound, the aldehyde is an aldehyde of the formula (III ') or (IV'), and the aldehyde and the base in advance Mixing to form salts of formula III or IV. Formula III ' Formula IV ' Formula III Formula IV In the above formulas III ', IV', III and IV, Me is a methyl group, X is any one of a lithium atom, a sodium atom and a potassium atom. 8. The process according to claim 1, 2, 6 or 7, comprising the step of neutralizing the salt of the derivative obtained by the reductive alkylation reaction with an acid to convert the derivative into a vitreous. The method of claim 12, wherein the acid is one or more acids selected from hydrochloric acid, sulfuric acid and acetic acid. 13. The process of claim 12, wherein neutralization with acid in a reductive alkylation reaction is effected during the hydrogenation reaction. 8. Process according to claim 1, 2, 6 or 7, wherein the hydrogenation reaction temperature in the reductive alkylation reaction is from 0 to 60 ° C. 8. The process according to claim 1, 2, 6 or 7, comprising the step of maintaining stirring at 40 DEG C or less for at least 10 minutes before the hydrogenation reaction in the reductive alkylation reaction. The process of claim 1, 2, 6 or 7 wherein the catalyst is one or more catalysts selected from palladium carbon, palladium black, Raney nickel and platinum carbon. 8. The process of claim 1, 2, 6 or 7, wherein the reductive alkylation reaction is carried out in a solvent and the solvent is methanol. 8. The process according to claim 1, 2, 6 or 7, comprising hydrogenation by hydrogen partial pressure of 0.1 to 10 MPa in a reductive alkylation reaction. 8. The method according to claim 1, 2, 6 or 7, wherein the derivative is a vitreous and comprises a step of crystallizing the derivative with a water-alcohol mixed solvent after the step of producing the vitreous. The method of claim 20, wherein the alcohol is methanol.